The present invention relates to compounds useful for treating pathological states which arise from or are exacerbated by cell proliferation, to pharmaceutical compositions comprising these compounds, and to methods of inhibiting cell proliferation in a mammal.
Neoplastic diseases, characterized by the proliferation of cells which are not subject to normal cell proliferating controls, are a major cause of death in humans and other mammals. Cancer chemotherapy has provided new and more effective drugs to treat these diseases and has also demonstrated that drugs which disrupt microtubule synthesis are effective in inhibiting the proliferation of neoplastic cells.
Microtubules play a key role in the regulation of cell architecture, metabolism, and division. The microtubule system of eucaryotic cells comprises a dynamic assembly and disassembly matrix in which heterodimers of tubulin polymerize to form microtubules in both normal and neoplastic cells. Within noeplastic cells, tubulin is polymerized into microtubules which form the mitotic spindle. The microtubules are then depolymerized when the mitotic spindle""s use has been fulfilled. Agents which disrupt the polymerization or depolymerization of microtubules in neoplastic cells, thereby inhibiting the proliferation of these cells, comprise some of the most effective cancer chemotherapeutic agents in use.
Because of the pivotal role played by cell proliferation, agents which inhibit microtubule polymerization have been the subject of active current research for their clinical potential. See, for example, U.S. Pat. Nos. 5,767,283, 5,721,246, 5,610,320, FR 2,729,421-A1, and WO96/27295. But there is still a need for tubulin polymerization-inhibiting compounds with modified or improved profiles of activity.
In one embodiment of the present invention are disclosed microtubule polymerization-inhibiting compounds represented by formula (I) 
or pharmaceutically acceptable salts or prodrugs thereof, wherein
L1 is selected from the group consisting of
(1) xe2x80x94S(O)2Oxe2x80x94,
(2) xe2x80x94OS(O)2xe2x80x94,
(3) xe2x80x94NR7SO2xe2x80x94, wherein R7 is selected from the group consisting of
(a) hydrogen,
(b) hydroxy,
(c) amidinyl,
(d) a nitrogen-protecting group,
(e) alkanoyl,
(f) alkyl,
(g) alkenyl,
(h) alkynyl,
(i) cycloalkyl,
(j) cycloalkylalkyl,
(k) cycloalkenyl,
(l) cycloalkenylalkyl,
(m) aryloyl,
(n) alkoxy,
wherein (e)-(n) can be optionally substituted with one, two, or three substituents independently selected from the group consisting of
(i) hydroxyl,
(ii) halo,
(iii) cyano,
(iv) azido,
(v) carboxy,
(vi) amidinyl,
(vii) alkyl,
(viii) aryl,
(ix) oxo,
(x) heteroaryl,
(xi) heterocycloalkyl,
(xii) xe2x80x94NRcRd, wherein Rc and Rd are independently selected from the group consisting of
(1xe2x80x2) hydrogen,
(2xe2x80x2) alkyl,
(3xe2x80x2) aryl, and
(4xe2x80x2) alkoxyalkyl, and
(xiii) -(alkylene)-NRcRd,
wherein for (x) and (xi), the heteroaryl and the heterocycloalkyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(1xe2x80x2) alkyl, and
(2xe2x80x2) a nitrogen protecting group,
(o) heterocycloalkyloyl, wherein the heterocycloalkyloyl can be optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of
(i) alkyl, and
(ii) a nitrogen protecting group, and
(p) xe2x80x94(CH2)xNRARB, wherein x is 0-6, and RA and RB are independently selected from the group consisting of
(i) hydrogen,
(ii) alkyl,
(iii) alkenyl,
(iv) alkynyl,
(v) cycloalkyl,
(vi) cycloalkylalkyl,
(vii) cycloalkenyl, and
(viii) cycloalkenylalkyl,
(4) xe2x80x94SO2NR7xe2x80x94, wherein R7 is defined above,
(5) xe2x80x94S(O)CR12R13xe2x80x94, wherein R12 and R13 are independently selected from the group consisting of
(a) hydrogen,
(b) alkyl,
(c) alkenyl, and
(d) alkynyl,
(6) xe2x80x94SO2CR12R13xe2x80x94,
(7) xe2x80x94SCR12R13xe2x80x94,
(8) xe2x80x94CR12R13S(O)xe2x80x94,
(9) xe2x80x94CR12R13SO2xe2x80x94, and
(10) xe2x80x94CR12R13Sxe2x80x94,
wherein (1)-(10) are shown with their left ends attached to R1 and their right ends attached to the phenyl ring;
R1 is aryl or heteroaryl, wherein the aryl or the heteroaryl can be optionally substituted with 1, 2, 3, 4, or 5 substituents independently selected from the group consisting of
(a) oxo,
(b) azido,
(c) carboxy,
(d) carboxaldehyde,
(e) cyano,
(f) halo,
(g) hydroxy,
(h) nitro,
(i) perfluoroalkyl,
(j) perfluoroalkoxy,
(k) alkyl,
(l) alkenyl,
(m) alkynyl,
(n) alkanoyloxy,
(o) alkoxycarbonyl,
(p) cycloalkyl,
(q) cycloalkylalkyl,
(r) cycloalkenyl,
(s) cycloalkenylalkyl,
(t) alkanoyl,
(u) alkoxy,
(v) cycloalkoxy,
(w) aryloxy,
(x) heteroaryloxy,
(y) thioalkoxy
(z) alkylsulfinyl,
(aa) alkylsulfonyl,
(bb) xe2x80x94NR8R9, wherein R8 and R9 are independently selected from the group consisting of
(i) hydrogen
(ii) alkyl,
(iii) arylalkyl, and
(iv) alkanoyl, wherein the alkanoyl can be optionally substituted with 1 or 2 substituents independently selected from the group consisting of
(1xe2x80x2) halo
(2xe2x80x2) hydroxy, and
(3xe2x80x2) xe2x80x94NR10R11 wherein R10 and R11 are independently hydrogen or alkyl, and
(cc) xe2x80x94SO2NR8R9, wherein R8 and R9 are defined above;
R2 and R6 are independently selected from the group consisting of
(1) hydrogen,
(2) alkyl,
(3) alkoxy,
(4) thioalkoxy; and
(5) hydroxy, and
R3, R4, and R5 are independently selected from the group consisting of
(1) alkyl,
(2) alkoxy,
(3) thioalkoxy, and
(4) hydroxy;
all of the foregoing with the proviso that combinations wherein L1 is xe2x80x94NR7SO2xe2x80x94 and R1 is
(1) unsubstituted or substituted 1H-indoly-7-yl,
(2) phenyl which is 2-monosubstituted with xe2x80x94NR8R9,
(3) pyrid-3-yl which is 2-monosubstituted with xe2x80x94NR8R9, or
(4) pyrimidin-5-yl which is 4-monosubstituted with xe2x80x94NR8R9, are excluded therefrom.
In a preferred embodiment of the invention are compounds wherein L1 is xe2x80x94SO2NR7xe2x80x94, and R7 is defined above.
In another preferred embodiment of the invention are compounds wherein R1 is aryl.
In another preferred embodiment of the invention are compounds wherein R1 optionally substituted heteroaryl, particularly N-methyl substituted 1H-indolyl.
In another preferred embodiment of the invention are compounds wherein R7 is substituted alkanoyl, substituted aryloyl, or optionally substituted heterocycloalkyloyl.
In another preferred embodiment of the invention are compounds wherein L1 is xe2x80x94NR7SO2xe2x80x94, and R7 is defined above.
In another preferred embodiemtn of the invention are compounds wherein L1 is xe2x80x94SO2CR12R13xe2x80x94.
In another preferred embodiemtn of the invention are compounds wherein L1 is xe2x80x94SCR12R13xe2x80x94.
In another preferred embodiemtn of the invention are compounds wherein L1 is xe2x80x94CR12R13S(O)xe2x80x94.
In another preferred embodiemtn of the invention are compounds wherein L1 is xe2x80x94CR12R13SO2xe2x80x94.
In another preferred embodiemtn of the invention are compounds wherein L1 is xe2x80x94CR12R13Sxe2x80x94.
In yet another preferred embodiment of the invention are compounds wherein L1 is xe2x80x94OSO2xe2x80x94.
In still yet another preferred embodiment of the invention are compounds wherein L1 is xe2x80x94SO2Oxe2x80x94.
In another embodiment of the invention are disclosed methods of inhibiting polymerization of tubulin in a mammal in recognized need of such treatment comprising administering an effective amount of a compound having formula (I).
In yet another embodiment of the invention are disclosed methods of treating cancer in a mammal in recognized need of such treatment comprising administering an effective amount of a compound having formula (I).
In still yet another embodiment of the invention are disclosed pharmaceutical compositions containing compounds having formula (I).
Definition of Terms
The term xe2x80x9calkanoyl,xe2x80x9d as used herein, refers to an alkyl group attached to the parent molecular group through a carbonyl group. The alkanoyl groups of this invention can be optionally substituted.
The term xe2x80x9calkanoyloxy,xe2x80x9d as used herein, refers to an alkanoyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9calkenyl,xe2x80x9d as used herein, refers to a monovalent straight or branched chain group of two to six carbon atoms containing at least one carbon-carbon double bond. The alkenyl groups of this invention can be optionally substituted.
The term xe2x80x9calkoxy,xe2x80x9d as used herein, refers to an alkyl group attached to the parent molecular group through an oxygen atom. The alkoxy groups of this invention can be optionally substituted.
The term xe2x80x9calkoxyalkyl,xe2x80x9d as used herein, refers to an alkoxy group attached to the parent molecular moiety through an alkyl group.
The term xe2x80x9calkoxycarbonyl,xe2x80x9d as used herein, refers to an alkoxy group attached to the parent molecular group through a carbonyl group.
The term xe2x80x9calkyl,xe2x80x9d as used herein, refers to a monovalent group of one to six carbon atoms derived from a straight or branched chain saturated hydrocarbon. The alkyl groups of this invention can be optionally substituted.
The term xe2x80x9calkylating agent,xe2x80x9d as used herein, represents a reagent capable of donating an alkyl group during the course of a reaction. Examples of alkylating agents include methyl triflate, dimethyl sulfate, iodomethane, bromobutane, bromopropane, and the like.
The term xe2x80x9calkylene,xe2x80x9d as used herein, refers to a saturated divalent hydrocarbon group derived from a straight or branched chain saturated hydrocarbon by the removal of two hydrogen atoms.
The term xe2x80x9calkylsulfinyl,xe2x80x9d as used herein, refers to an alkyl group attached to the parent molecular group through an xe2x80x94S(O)xe2x80x94 group.
The term xe2x80x9calkylsulfonyl,xe2x80x9d as used herein, refers to an alkyl group attached to the parent molecular group through an xe2x80x94SO2xe2x80x94 group.
The term xe2x80x9calkynyl,xe2x80x9d as used herein, refers to a monovalent straight or branched chain group of two to six carbon atoms containing at least one carbon-carbon triple bond The alkynyl groups of this invention can be optionally substituted.
The term xe2x80x9camidinyl,xe2x80x9d as used herein, refers to an xe2x80x94NR10R11 group, wherein R10 and R11 are defined above, connected to the parent molecular group through an imine.
The term xe2x80x9caryl,xe2x80x9d as used herein, refers to a mono- or bicyclic-carbocyclic ring system having at least one aromatic ring. Aryl groups are exemplified by those derived from phenyl, naphthyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, azulenyl, and troponyl. Bicyclic aryl groups of this invention can be attached to the parent molecular group through either a saturated or unsaturated part of the group. The aryl groups of this invention can be optionally substituted.
The term xe2x80x9carylalkyl,xe2x80x9d as used herein, refers to an alkyl group to which is attached at least one aryl group.
The term xe2x80x9caryloxy,xe2x80x9d as used herein, refers to an aryl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9caryloyl,xe2x80x9d as used herein, refers to an aryl group attached to the parent molecular moiety through a carbonyl group. The aryloyl groups of this invention can be optionally substituted.
The term xe2x80x9cazido,xe2x80x9d as used herein, refers to xe2x80x94N3.
The term xe2x80x9cbase,xe2x80x9d as used herein, represents a reagent capable of accepting protons during the course of a reaction. Examples of bases include carbonates such as potassium carbonate, potassium bicarbonate sodium carbonate, sodium bicarbonate, and cesium carbonate; halides such as cesium fluoride; phosphates such as potassium phosphate, potassium dihydrogen phosphate, and potassium hydrogen phosphate; hydroxides such as lithium hydroxide, sodium hydroxide, and potassium hydroxide; disilylamides such as lithium hexamethyldisilazide, potassium hexamethyldisilazide, and sodium hexamethyldisilazide; trialkylamines such as triethylamine and diisopropylamine; heterocyclic amines such as imidazole, pyridine, pyridazine, pyrimidine, and pyrazine; bicyclic amines such as DBN and DBU; and hydrides such as lithium hydride, sodium hydride, and potassium hydride. The base chosen for a particular conversion depends on the nature of the starting materials, the solvent or solvents in which the reaction is conducted, and the temperature at which the reaction is conducted.
The term xe2x80x9ccarboxaldehyde,xe2x80x9d as used herein, refers to xe2x80x94CHO.
The term xe2x80x9ccarbonyl,xe2x80x9d as used herein, refers to xe2x80x94C(O)xe2x80x94.
The term xe2x80x9ccarboxy,xe2x80x9d as used herein, refers to xe2x80x94CO2H.
The term xe2x80x9ccyano,xe2x80x9d as used herein, refers to xe2x80x94CN.
The term xe2x80x9ccycloalkenyl,xe2x80x9d as used herein, refers to a monovalent cyclic or bicyclic hydrocarbon of four to twelve carbon atoms having at least one carbon-carbon double bond.
The term xe2x80x9ccycloalkenylalkyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, to which is attached at lease one cycloalkenyl group.
The term xe2x80x9ccycloalkyl,xe2x80x9d as used herein, refers to a monovalent saturated cyclic hydrocarbon group of three to twelve carbon atoms.
The term xe2x80x9ccycloalkylalkyl,xe2x80x9d as used herein, refers to an alkyl group, as defined herein, to which is attached at lease one cycloalkyl group.
The term xe2x80x9chalo,xe2x80x9d as used herein, refers to xe2x80x94F, xe2x80x94Cl, xe2x80x94Br or xe2x80x94I.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, refers to a cyclic aromatic group having five or six ring atoms, wherein at least one ring atom is selected from the group consisting of oxygen, sulfur, and nitrogen, and the remaining ring atoms are carbon. The nitrogen atoms can be optionally quaternized, and the sulfur atoms can be optionally oxidized. Heteroaryl groups of this invention include those derived from furan, imidazole, isothiazole, isoxazole, oxadiazole, oxazole, 1,2,3-oxadiazole, pyrazine, pyrazole, pyridazine, pyridine, pyrimidine, pyrroline, thiazole, 1,3,4-thiadiazole, thiene, triazole, and tetrazole.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, also includes bicyclic or tricyclic rings, wherein any of the aformentioned heteroaryl rings is fused to one or two rings independently selected from the group consisting of an aryl ring, a cycloalkyl ring, a cycloalkenyl ring, and another monocyclic heteroaryl or heterocyaloalkyl ring. These bicyclic or tricyclic heteroaryls include those derived from benzo[b]furan, benzo[b]thiene, benzimidazole, cinnoline, imidazo[4,5-c]pyridine, quinazoline, thieno[2,3-c]pyridine, thieno[3,2-b]pyridine, thieno[2,3-b]pyridine, indolizine, imidazo[1,2-a]pyridine, quinoline, isoquinoline, phthalazine, quinoxaline, naphthyridine, quinolizine, indole, isoindole, indazole, indoline, benzoxazole, benzopyrazole, benzothiozole, imidazo[1,5-a]pyridine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyrimidine, imidazo[1,2-c]pyrimidine, imidazo[1,5-a]pyrimidine, imidazo[1,5-c]pyrimidine, pyrrolo[2,3-b]pyridine, pyrrolo[2,3-c]pyridine, pyrrolo[3,2-c]pyridine, pyrrolo[3,2-b]pyridine, pyrrolo[2,3-d]pyrimidine, pyrrolo[3,2-d]pyrimidine, pyrrolo[2,3-b]pyrazine, pyrazolo[1,5-a]pyridine, pyrrolo[1,2-b]pyridazine, pyrrolo[1,2-c]pyrimidine, pyrrolo[1,2-a]pyrimidine, pyrrolo[1,2-a]pyrazine, triazo[1,5-a]pyridine, pteridine, purine, carbazole, acridine, phenazine, phenothiazine, phenoxazine, 1,2-dihydropyrrolo[3,2,1-hi]indole, indolizine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[1,2-a]pyridine, pyrido[1,2-a]indole, 10,11-dihydro-5H-dibenzo[b,e][1,4]diazepine, 5,11-dihydrodibenzo[b,e][1,4]oxazepine, and 2(1H)-pyridinone. The bicyclic or tricyclic heteroaryl rings and can be attached to the parent molecular group through either the heretoaryl group itself or the aryl, cycloalkyl, cycloalkenyl, or heterocycloalkyl group to which it is fused.
The term xe2x80x9cheteroaryl,xe2x80x9d as used herein, also includes compounds having formula 
wherein W* is xe2x80x94Oxe2x80x94 or xe2x80x94NR10xe2x80x94, wherein R10 is defined above, Y* is xe2x80x94C(O)xe2x80x94 or xe2x80x94(C(R10)(R11))vxe2x80x94, wherein R10 and R11 are defined above, and v is 1, 2, or 3, and Z* is xe2x80x94CH2xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94CH2S(O)txe2x80x94, wherein t is zero, one or two, xe2x80x94CH2Oxe2x80x94, xe2x80x94CH2NR10xe2x80x94, or xe2x80x94NR10xe2x80x94, wherein R10 is defined above. The heteroaryl groups of this invention can be optionally substituted.
The term xe2x80x9cheteroaryloxy,xe2x80x9d as used herein, refers to a heteroaryl group attached to the parent molecular group through an oxygen atom. The heteroaryloxy groups of this invention can be optionally substituted.
The term xe2x80x9cheterocycloalkyl,xe2x80x9d as used herein, refers to a non-aromatic five-, six- or seven-membered ring having between one and three heteroatoms independently selected from oxygen, sulfur, and nitrogen, wherein each 5-membered ring has zero to one double bonds and each six-membered ring has zero to 2 double bonds. Representative heterocycloalkyl groups include 3,4-dihydropyridinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, tetrahydrofuryl, and 1,2,3,4-tetrahydropyridinyl. The heterocycloalkyl groups of this invention can be optionally substituted.
The term xe2x80x9cheterocycloalkyloyl,xe2x80x9d as used herein, refers to a heterocycloalkyl group attached to the parent molecular moiety through a carbonyl group.
The term xe2x80x9chydroxy,xe2x80x9d as used herein, refers to xe2x80x94OH.
The term xe2x80x9cimine,xe2x80x9d as used herein, refers to xe2x80x94C(xe2x95x90NR21)xe2x80x94, wherein R21 is defined above.
The term xe2x80x9cnitro,xe2x80x9d as used herein, refers to xe2x80x94NO2.
The term xe2x80x9cnitrogen-protecting group,xe2x80x9d as used herein, refers to groups intended to protect an amino group against undesirable reactions during synthetic procedures. Commonly used nitrogen-protecting groups are disclosed in Greene, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d (John Wiley and Sons, New York (1991)). Common N-protecting groups comprise (a) acyl groups such as formyl, acetyl, propionyl, pivaloyl, tert-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, xcex1-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl and 4-nitrobenzoyl, (b) sulfonyl groups such as benzenesulfonyl, and para-toluenesulfonyl, (c) carbamate forming groups such as benzyloxycarbonyl, para-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, xcex1,xcex1-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl, tert-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2,-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxy carbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl, (d) arylalkyl groups such as benzyl, triphenylmethyl, and benzyloxymethyl, and (e) silyl groups such as trimethylsily. Preferred N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, tert-butylacetyl, phenylsulfonyl, benzyl, tert-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
The term xe2x80x9coxo,xe2x80x9d as used herein, refers to (xe2x95x90O).
The term xe2x80x9cperfluoroalkyl,xe2x80x9d as used herein, refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluorine atoms.
The term xe2x80x9cperfluoroalkoxy,xe2x80x9d as used herein, refers to a perfluoroalkyl group attached to the parent molecular group through an oxygen atom.
The term xe2x80x9cperfluoroalkyl,xe2x80x9d as used herein, refers to an alkyl group in which all of the hydrogen atoms have been replaced by fluoride atoms.
The term xe2x80x9cpharmaceutically acceptable salt,xe2x80x9d as used herein, refers to salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well-known in the art. For example, S. M. Berge, et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66: 1 et seq, hereby incorporated by reference. The salts may be prepared in situ during the final isolation and purification of the compounds of the invention or separately by reacting a free base function with a suitable acid. Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsufonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate and undecanoate. Also, the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates such as dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halides such as decyl, lauryl, myristyl, and stearyl chlorides, bromides and iodides; and arylalkyl halides such as benzyl and phenethyl bromides. Water or oil-soluble or dispersible products are thereby obtained. Examples of acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid, and citric acid.
Basic addition salts can be prepared in situ during the final isolation and purification of compounds of this invention by reacting a carboxylic acid-containing moiety with a suitable base such as the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptable metal cation or with ammonia or an organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include, but are not limited to, cations based on alkali metals or alkaline earth metals such as lithium, sodium, potassium, calcium, magnesium and aluminum salts and the like and nontoxic quaternary ammonia and amine cations including ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, and ethylamine. Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine, diethanolamine, piperidine, and piperazine.
The term xe2x80x9cpharmaceutically acceptable prodrugs,xe2x80x9d as used herein refers to, those prodrugs of the compounds of the present invention which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible, of the compounds of the invention.
The term xe2x80x9cprodrug,xe2x80x9d as used herein, represents compounds which are rapidly transformed in vivo to parent compounds having formula (I), for example, by hydrolysis in blood. A thorough discussion is provided in T. Higuchi and V. Stella, Prodrugs as Novel Delivery Systems, Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference. Particularly preferred prodrugs of the invention include compounds having formula (I), wherein a nitrogen, hydroxy, or thiol group has attached thereto an aminoacyl, bisaminoacyl (2-mer), or trisaminoacyl (3-mer) group optionally capped with a carboxyl protecting group. The term xe2x80x9caminoacyl,xe2x80x9d as used herein, refers to a group derived from naturally or unnaturally occuring amino acids. Representative aminoacyl groups include those derived from glycine, alanine, xcex2-alanine, valine, leucine, iso-leucine, methionine, serine, threonine, cysteine, phenylalanine, and tyrosine in the racemic, D or L configurations. The aminoacyl groups of this invention can be optionally substituted. The terms xe2x80x9cbisaminoacylxe2x80x9d and xe2x80x9ctrisaminoacyl,xe2x80x9d as used herein, refer to di- and tri-aminoacyl groups, respectively. Representative examples of bisaminoacyl and trisaminoacyl groups include 2-mers and 3-mers derived from glycine, alanine, xcex2-alanine, valine, leucine, iso-leucine, methionine, serine, threonine, cysteine, phenylalanine, and tyrosine in the racemic, D or L configurations.
The term xe2x80x9cthioalkoxy,xe2x80x9d as used herein, refers to an alkyl group attached to the parent molecular group through a sulfur atom.
The present invention contemplates metabolites formed by in vivo biotransformation of compounds having formula (I). The term xe2x80x9cmetabolite,xe2x80x9d as used herein, refers to compounds formed by in vivo biotransformation of compounds having formula (I) by oxidation, reduction, hydrolysis, or conjugation. The present invention also contemplates compounds which undergo in vivo biotransformation such as by oxidation, reduction, hydrolysis, or conjugation to form compounds having formula (I). A thorough discussion of biotransformation is provided in Goodman and Gilman""s, The Pharmacological Basis of Therapeutics, seventh edition, hereby incorporated by reference.
Asymmetric or chiral centers may exist in the compounds of the present invention. The present invention contemplates the various stereoisomers and mixtures thereof. Individual stereoisomers of compounds of the present invention are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of mixtures of enantiomeric compounds followed by resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a racemic mixture of enantiomers to a chiral auxiliary, separation of the resulting diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
Geometric isomers may also exist in the compounds of the present invention. The present invention contemplates the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond.
Compounds falling within the scope of formula (I) include, but are not limited to
4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
3,4-dimethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
4-trifluoromethoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
4-trifluoromethyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
4-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
4-amino-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
4-((2-chloroacetyl)amino)-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
2-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
4-methoxy-3-nitro-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
3-amino-4-methoxy-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
1-formyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,
N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,
5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,
1-methyl-N-(3,4,5-trimethoxyphenyl)indoline-5-sulfonamide,
1-methyl-5-nitro-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,
5-amino-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,
5-amino-N-(3,4,5-trimethoxyphenyl)-1H-indole-3-sulfonamide,
N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N,1-dimethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
3,4,5-trimethoxy-N-(4-methoxyphenyl)benzenesulfonamide,
N-(3-hydroxy-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,
N-(1-methyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,
N-(4-(dimethylamino)phenyl)-3,4,5-trimethoxybenzenesulfonamide,
N-(4-fluoro-3-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,
3,4,5-trimethoxy-N-(4-(trifluoromethoxy)phenyl)benzenesulfonamide,
3,4,5-trimethoxy-N-(2,3,4,5,6-pentafluorophenyl)benzenesulfonamide,
N-(3-amino-4-methoxyphenyl)-3,4,5-trimethoxybenzenesulfonamide,
3,4,5-trimethoxy-N-(1-methyl-1H-indol-4-yl)benzenesulfonamide,
3,4,5-trimethoxy-N-(1-methyl-1H-indol-6-yl)benzenesulfonamide,
N-(1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,
N-(1,2-dimethyl-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,
N-(3-chloro-1H-indol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,
N-(1H-indazol-5-yl)-3,4,5-trimethoxybenzenesulfonamide,
3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-6-yl)benzenesulfonamide,
3,4,5-trimethoxy-N-(1-methyl-1H-benzimidazol-5-yl)benzenesulfonamide,
3,4,5-trimethoxy-N-methyl-N-(1-methyl-1H-indol-5-yl) benzenesulfonamide, 3,4,5-trimethoxy-N-(2-(dimethylamino)ethyl)-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,
1H-indol-5-yl 3,4,5-trimethoxybenzenesulfonate,
(3,4,5-trimethoxyphenyl) 4-methoxybenzenesulfonate,
3,4,5-trimethoxyphenyl) 4-methylbenzenesulfonate,
1H-indol-5-yl 3,4,5-trimethoxybenzenesulfonate,
3,4,5-trimethoxyphenyl) 3-amino-4-methoxybenzenesulfonate,
(3,4,5-trimethoxyphenyl)-4-(dimethylamino)benzenesulfonate,
4-methylphenyl 3,4,5-trimethoxybenzenesulfonate,
3,4,5-trimethoxyphenyl 1-methyl-5-indolinesulfonate, and
4-methoxyphenyl 3,4,5-trimethoxybenzenesulfonate.
tert-butyl 2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)ethylcarbamate,
N-(2-hydroxyethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,
N-(2,3-dihydro-1,4-benzodioxin-6-yl)-3,4,5-trimethoxybenzenesulfonamide,
N-(2-aminoethyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,
3-amino-4-methoxy-N-methyl-N-(3,4,5-trimethoxyphenyl)benzenesulfonamide,
1-ethyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-acetyl-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,
3,4,5-trimethoxy-N-(6-quinolinyl)benzenesulfonamide,
N-(2-hydroxyethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-(2-fluoroethyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-ethyl-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
4-nitrophenyl-3,4,5-trimethoxybenzenesulfonate,
4-aminophenyl-3,4,5-trimethoxybenzenesulfonate,
4-dimethylaminophenyl-3,4,5-trimethoxybenzenesulfonate,
3,4,5-trimethoxyphenyl 6-methoxy-3-pyridinesulfonate,
1-methyl-2-oxo-1,2-dihydro-4-pyridinyl 3,4,5-trimethoxybenzenesulfonate.
3,4,5-trimethoxyphenyl 3-((3-aminopropanoyl)amino)-4-methoxybenzenesulfonate,
3,4,5-trimethoxyphenyl 3-(((2R)-2-aminopropanoyl)amino)-4-methoxybenzenesulfonate,
3,4,5-trimethoxyphenyl 3-(((2R)-2-amino-3-methylbutanoyl)amino)-4-methoxybenzenesulfonate,
N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-(((2S)-1-methylpyrrolidinyl)carbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-(dimethylamino)-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-amino-3-methylbutanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-((2S)-2-methylamino)propanoyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-amino-2-phenylethanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-amino-3-phenylpropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-((2S)-pyrrolidinylcarbonyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2,6-diaminohexanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-amino-3-(1H-imidazol-5-yl)propanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
(2S)-2-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoic acid,
(3S)-3-amino-4-oxo-4-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)butanoic acid,
(2S)-2-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoic acid,
(4S)-4-amino-5-oxo-5-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)pentanoic acid,
N-((bis(2-methoxyethyl)amino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-(4-morpholinylacetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1-methyl-N-((4-methyl-1-piperazinyl)acetyl)-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-(4-(aminomethyl)benzoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfanyl)benzene,
1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfinyl)benzene,
1,2,3-trimethoxy-5-((4-methoxybenzyl)sulfonyl)benzene,
1,2,3-trimethoxy-5-((1-(4-methoxyphenyl)-1-methylethyl)sulfonyl)benzene,
2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfanyl)methyl)aniline,
2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfinyl)methyl)aniline,
2-methoxy-5-(((3,4,5-trimethoxyphenyl)sulfonyl)methyl)aniline,
2-methoxy-5-(1-methyl-1-((3,4,5-trimethoxyphenyl)sulfonyl)ethyl)aniline,
1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfanyl)methyl)benzene,
1,2,3-trimethoxy-5-(((4-methoxyphenyl)sulfonyl)methyl)benzene,
1,2,3-trimethoxy-5-(1-((4-methoxyphenyl)sulfonyl)-1-methylethyl)benzene,
2-methoxy-5-((3,4,5-trimethoxybenzyl)sulfonyl)aniline,
2-methoxy-5-((1-methyl-1-(3,4,5-trimethoxyphenyl)ethyl)sulfonyl)aniline, 1,2,3-trimethoxy-5-((phenylsulfonyl)methyl)benzene,
N-(2-aminoacetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-(2-aminoacetyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,
N-((2S)-2-aminopropanoyl]-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-((2S)-2-aminopropanoyl]-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,
N-(3-aminopropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide,
N-(3-aminopropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide,
(2S)-2-amino-N-((1S)-1-methyl-2-oxo-2-(3,4,5-trimethoxy((1-methyl-1H-indol-5-yl)sulfonyl)anilino)ethyl)propanamide,
(2S)-2-amino-N-((1S)-1-methyl-2-((1-methyl-1H-indol-5-yl)((3,4,5-trimethoxyphenyl)sulfonyl)amino)-2-oxoethyl)propanamide,
N-((2S)-2-amino-3-hydroxypropanoyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide, and
N-((2S)-2-amino-3-hydroxypropanoyl)-3,4,5-trimethoxy-N-(1-methyl-1H-indol-5-yl)benzenesulfonamide.
A more preferred compound for the practice of the present invention is N-((dimethylamino)acetyl)-1-methyl-N-(3,4,5-trimethoxyphenyl)-1H-indole-5-sulfonamide.
Determination of Biological Activity
Compounds of this invention were tested in a 48-hour cellular proliferation assay which uses human colon adenocarcinoma, MDR positive (HCT-15) cells, and human lung large cell carcinoma, MDR negative (NCI-H460) cells, in the 96-well microtitre format described in Skehan P., et al. New Colorimetric Cytotoxicity Assay for Anticancer Drug Screening. 1990, J. Natl. Cancer Inst. 82:1107-1112, hereby incorporated by reference. Briefly, the wells of a microtitre plate were charged sequentially with cultured cells and compounds of the invention (1.0xc3x9710xe2x88x924 to 1.0xc3x9710xe2x88x9211 M in 10% DMSO prepared by dissolving compounds of the invention in DMSO and adding 11 xcexcL of the DMSO solution to 100 xcexcL of culture medium for a final DMSO concentration of 10%). Two of the following controls were also present in each microtitre plate: a solvent (DMSO) control without drug that yielded a 0% inhibition level and a trichloroacetic acid-treated well that yielded a 100% inhibition level. The cells were grown in culture (37xc2x0 C., 5% CO2 atmosphere) for 48 hours then fixed by the addition of trichloroacetic acid. The wells were stained with sulforhodamine, washed with 1% acetic acid, and treated with 0.01M tris buffer (100 xcexcL) to solubilize the adherent dye. The absorbance of the dye solution was measured with a Molecular Devices SpectraMax340 plate reader. The percent inhibition values were obtained by calculating the proportional response of the experimental values to the absorbance values of the controls. The results for representative examples of compounds having formula (I) are shown in Table 1.
As shown by the data in Table 1, the compounds of the invention, including, but not limited to, those specified in the examples, are useful for the treatment of disease caused or exascerbated by cell proliferation. As cell proliferation inhibitors, these compounds are useful in the treatment of both primary and metastatic solid tumors and carinomas of the breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder, bile ducts, small intestine, urinary tract including kidney, bladder and urothelium, female genital tract including cervix, uterus, ovaries, choriocarcinoma, and gestational trophoblastic disease, male genital tract including prostate, seminal vesicles, testes, and germ cell tumors, endocrine glands including thyroid, adrenal, and pituitary, skin including hemangiomas, melanomas, sarcomas arising from bone or soft tissues including Kaposi""s sarcoma, tumors of the brain, nerves, and eyes, meninges including astrocytomas, gliomas, glioblastomas, retinoblastomas, neuromas, neuroblastomas, Schwannomas and meningiomas, solid tumors arising from hematopoietic malignancies including leukemias and chloromas, plasmacytomas, plaques, tumors of mycosis fungoides, cutaneous T-cell lymphoma/leukemia, lymphomas including Hodgkin""s and non-Hodgkin""s lymphomas, prophylaxis of autoimmune diseases including rheumatoid, immune and degenerative arthritis, ocular diseases including diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration, hypoxia, abnormal neovascularization conditions of the eye, skin diseases including psoriasis, blood vessel diseases including hemagiomas and capillary proliferation within atherosclerotic plaques, Osler-Webber Syndrome, myocardial angiogenesis, plaque neovascularization, telangiectasia, hemophiliac joints, angiofibroma, and wound granulation.
The compounds of the present invention may also be useful for the prevention of metastases from the tumors described above either when used alone or in combination with radiotherapy and/or other chemotherapeutic treatments conventionally administered to patients for treating cancer. For example, when used in the treatment of solid tumors, compounds of the present invention may be administered with chemotherapeutic agents such as alpha inteferon, COMP (cyclophosphamide, vincristine, methotrexate, and prednisone), etoposide, mBACOD (methortrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine, and dexamethasone), PRO-MACE/MOPP (prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, paclitaxel, etoposide/mechlorethamine, vincristine, prednisone, and procarbazine), vincristine, vinblastine, angioinhibins, TNP-470, pentosan polysulfate, platelet factor 4, angiostatin, LM-609, SU-101, CM-101, Techgalan, thalidomide, SP-PG, and the like. Other chemotherapeutic agents include alkylating agents such as nitrogen mustards (mechloethamine, melphan, chlorambucil, cyclophosphamide and ifosfamide), nitrosoureas including carmustine, lomustine, semustine and streptozocin, alkyl sulfonates including busulfan, triazines including dacarbazine, ethyenimines including thiotepa and hexamethylmelamine, folic acid analogs including methotrexate, pyrimidine analogues including 5-fluorouracil and cytosine arabinoside, purine analogs including 6-mercaptopurine and 6-thioguanine, antitumor antibiotics including actinomycin D, anthracyclines including doxorubicin, bleomycin, mitomycin C and methramycin, hormones and hormone antagonists including tamoxifen, cortiosteroids and miscellaneous agents including cisplatin and brequinar. For example, a tumor may be treated conventionally with surgery, radiation, or chemotherapy, and compounds having formula (I), then treated with additional compound having formula (I) to extend the dormancy of micrometastases and to stabilize and inhibit the growth of any residual primary tumor.
Methods of Treatment
The present invention also provides pharmaceutical compositions which comprise compounds of the present invention formulated together with one or more non-toxic pharmaceutically acceptable carriers. The pharmaceutical compositions may be specially formulated for oral administration in solid or liquid form, for parenteral injection, or for rectal administration.
The pharmaceutical compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), bucally, or as an oral or nasal spray. The term xe2x80x9cparenteralxe2x80x9d administration as used herein refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion.
Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil), and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
These compositions may also contain adjuvants such as preservative, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like, Prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
Injectable depot forms are made by forming microencapsule matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides) Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissues.
The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium just prior to use.
Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.
Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.
The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above-mentioned excipients.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.
Compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at room temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
Compounds of the present invention can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y. (1976), p. 33 et seq.
Dosage forms for topical administration of a compound of this invention include powders, sprays, ointments and inhalants. The active compound is mixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives, buffers, or propellants which may be required. Opthalmic formulations, eye ointments, powders and solutions are also contemplated as being within the scope of this invention. Actual dosage levels of active ingredients in the pharmaceutical compositions of this invention may be varied so as to obtain an amount of the active compound(s) that is effective to achieve the desired therapeutic response for a particular patient, compositions, and mode of administration. The selected dosage level will depend upon the activity of the particular compound, the route of administration, the severity of the condition being treated, and the condition and prior medical history of the patient being treated. However, it is within the skill of the art to start doses of the compound at levels lower than required for to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved.
Generally dosage levels of about 1 to about 50, more preferably of about 5 to about 20 mg of active compound per kilogram of body weight per day are administered orally to a mammalian patient. If desired, the effective daily dose may be divided into multiple doses for purposes of administration, e.g. two to four separate doses per day.
Synthetic Methods
The compounds and processes of the present invention will be better understood in connection with the following synthetic schemes, which illustrate methods by which the compounds of the invention may be prepared. The compounds having formula (I) may be prepared by a variety of synthetic routes. Representative procedures are shown in Scheme 1. The groups R1, R2, R3, R4, R5, R6, R12, R13, and L1, are as previously defined unless otherwise noted. It will be readily apparent to one of ordinary skill in the art that other compounds within formula (I) can be synthesized by substitution of the appropriate reactants and agents in the syntheses shown below. It will further be apparent to one skilled in the art that the selective protection and deprotection steps, as well as order of the steps themselves, can be carried out in varying order, depending on the nature of groups R1, R2, R3, R4, R5, R6, R12, R13, and L1, to successfully complete the syntheses of compounds having formula (I). Commonly used protecting groups are disclosed in Greene, xe2x80x9cProtective Groups In Organic Synthesis,xe2x80x9d John Wiley and Sons, New York (1981), hereby incorporated by reference. It will still further be apparent to one of ordinary skill in the art that the substituents R1, R2, R3, R4, R5, R6, R12, R13, and L1 can be determined by selection of the appropriate commercially available or known starting materials or introduced synthetically by known chemical methods such as those disclosed in Larock, xe2x80x9cComprehensive Organic Transformations. A Guide to Functional Group Preparations,xe2x80x9d VCH Publishers, New York (1989), hereby incorporated by reference.
Abbreviations
Abbreviations used in the descriptions of the schemes the examples are: THF for tetrahydrofuran; DMF for N,N-dimethylformamide; DMSO for dimethylsulfoxide; DEAD for diethyl azodicarboxylate; DIAD for diisopropyl azodicarboxylate; EDC for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; LDA for lithium diisopropylamide; TFA for trifluoroacetic acid; DMSO for dimethylsulfoxide; DMAP for 4-(N,N-dimethylamino)pyridine; HATU for O-(azabenzotriazole-1-yl)-N,N,Nxe2x80x2,Nxe2x80x2-tetramethyluroniumhexafluorophosphate; Boc for tert-butylcarbonyloxy; DPPA for diphenylphosphoryl azide; DCC for dicyclohexylcarbodiimide; HOOBT for 3-hydroxy-1,2,3-benzotriazin-4(3H)-one; HOBT for 1-hydroxybenzotriazole hydrate; EDCI for 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; CDI for 1,1xe2x80x2-carbonyldiimidazole; and DMAP for N,N-dimethylaminopyridine. 
As shown in Scheme 1, the compounds having formula (I) were prepared by reacting intermediate (i) with intermediate (ii), wherein X1 and X2 together are L1. With either (i) or (ii), X1 or X2 can be any conventional activated sulfonic acid, examples of which include sulfonyl halides, sulfonic acid anhydrides, and N-sulfonylimidazolides, preferably sulfonyl halides. Although the solvent used in the coupling reactions is not particularly limited, a solvent in which the starting materials are both soluble and which is little reactive with the materials is preferably used. Examples of such solvents are pyridine, triethylamine, THF, dioxane, benzene, toluene, diethyl ether, dichloromethane, DMF, DMSO, or mixtures thereof. When an acid is liberated with the progress of a reaction, such as when using a halide derivative of a sulfonic acid and an amine or alcohol, it is preferable that the reaction is carried out in the presence of a suitable deacidifying agent. For this reason, the use of a basic solvent such as pyridine or triethylamine is particularly preferred, although the reaction can be run in any of the aformentioned solvents with at least a stoichiometric amount of basic solvent present. Although the reactions generally proceed at room temperature, they can be run at lower or elevated temperatures, as needed. The reaction time is generally 30 minutes to 18 hours and can be arbitrarily selected depending on the types of starting materials and reaction temperature. When the product has a protected amino or hydroxyl group, the product, if necessary, can be converted to a compound having formula (I) having a free amino or hydroxyl group by a conventional deprotection method such as treatment with acid, piperidine, or catalytic hydrogenation in the presence of a catalyst such as palladium on carbon. When the compound having formula (I) has a nitro group, the nitro group can also be reduced. Although the reduction can be conducted by any conventional process, the conversion of a nitro group to an amine is preferably conducted by catalytic hydrogenation using palladium on carbon or platinum oxide as the catalyst or reduction using an acid together with zinc, iron, or tin. The catalytic reduction is conducted in an organic solvent such as methanol, ethanol, or THF under normal or elevated temperature. Groups on the compounds having formula (I) having endogenous or exogenous amino groups can optionally alkylated, formylated, acetylated or otherwise reacted with any number of amine-derivatization reagents well-known to those of ordinary skill in the art. For example, acidic Nxe2x80x94H groups can be reacted with alcohols under Mitsunobu conditions. Preferable Mitsunobu conditions include reacting the compounds having formula (I) with alcohols in the presence of a phosphine, preferably triphenylphosphine or tri n-butylphosphine and an activating agent such as DEAD or DIAD. Although the solvent to be used in the reaction is not particularly limited, polar, aprotic solvents such as THF or dioxane are particularly preferable for Mitsunobu reactions. The compounds having formula (I) can also be alkylated with any number of reagents well-known to those of ordinary skill in the art. For example, compounds having formula (I) can be reacted with an unsubstituted or substituted alkylating agent in the presence of a non-nucleophilic base such as sodium or potassium hydride or lithium, sodium, or potassium bis(trimethylsilyl)amide. Although the solvent to be used in the reaction is not particularly limited, polar, aprotic solvents such as THF, DMF, DMSO, or dioxane are particularly preferable for alkylation reactions. Compounds having formula (I) can be reacted with halogenation agents. Examples of halogenating agents include N-chlorosuccinamide, N-bromosuccinamide, 1,3-bibromo-5,5-dimethylhydantoin, N-bromoacetamide, bromine, chlorine, or iodine. Although the solvent to be used in the reaction is not particularly limited, chloroalkanes such as dichloromethane, chloroform, or carbon tetrachloride, halogenated aromatic rings such as chlorobenzene and dichlorobenzene, water, or organic acids, such as acetic acid, are particularly preferable. 
As shown in Scheme 2, compounds of formula (I) (R7 is H) can be intraconverted to compounds of formula (I) (R7 is an aminoacyl, bisaminoacyl (2-mer), or trisaminoacyl (3-mer) residue optionally capped with a carboxyl protecting group) by reaction with naturally or unnaturally occurring amino acids or with 2-mers and 3-mers derived from amino acids. Representative amino acids include N,N-dimethylglycine, N-methyl-L-proline, N,N-dimethyl-L-valine, N-tert-butoxycarbonyl)-L-valine, N-(tert-butoxy-carbonyl)-L-N-methylalanine, (S)-N-(tert-butoxycarbonyl)-2-phenylglycine, N-(tert-butoxycarbonyl)-L-phenylalanine, N-(tert-butoxycarbonyl)-L-proline, N,N-di-(tert-butoxycarbonyl)-L-lysine, N-(tert-butoxycarbonyl)-L-valine, N-(tert-butoxycarbonyl)-L-aspartic acid 1-tert-butyl ester, N-(tert-butoxycarbonyl)-L-aspartic acid 4-tert-butyl ester, N-(tert-butoxycarbonyl)-L-glutamic acid 1-tert-butyl ester, N-(tert-butoxycarbonyl)-L-glutamic acid 5-tert-butyl ester, (bis(2-methoxyethyl)amino)acetic acid, 4-morpholinylacetic acid, (4-methyl-1-piperazinyl)acetic acid, and 4-(((tert-butoxycarbonyl)amino)methyl)benzoic acid in the presence of base and an activating agent. Naturally occurring amino acids can be purchased commercially, while unnaturally occurring amino acids can be synthesized by methods well-known in the art. Representative bases include 4-pyrrolidinylpyridine, DMAP, and triethylamine. Examples of activating used in these reactions include DCC, EDCI, HOBT, and CDI. Typical solvents used in these reactions include dichloromethane, carbon tetrachloride, and chloroform. The reaction temperature is about 0xc2x0 C. to about 30xc2x0 C. and depends on the method chosen. Reaction times are typically about 2 to about 24 hours. In a preferred embodiment, compounds of formula (I) (R is H) in dichloromethane at room temperature are reacted with a naturally or unnaturally occurring amino acid in the presence of DCC and 4-pyrrolidinylpyridine for 16 hours to provide compounds of formula (I) (R7is an aminoacyl, bisaminoacyl (2-mer), or trisaminoacyl (3-mer) residue optionally capped with a carboxyl protecting group). 
Scheme 3 shows the method of preparation for compounds of formula (I) (L1 is xe2x80x94S(O)CR12R13xe2x80x94, xe2x80x94SO2CR12R13xe2x80x94, xe2x80x94SCR12R13xe2x80x94, xe2x80x94CR12R13S(O)xe2x80x94, xe2x80x94CR12R13SO2xe2x80x94, or xe2x80x94CR12R13Sxe2x80x94). Intermediates (iii) and (iv) (one of A1 and A2 is xe2x80x94CH2Cl; the other is SH) can be combined in the presence of base to provide the desired products. Examples of bases used in these reactions include KOH, NaOH, and LiOH. Representative solvents include N,N-dimethylformamide, dioxane, N-methylpyrrolidinone, and mixtures thereof. The reaction temperature is about 25xc2x0 C. to about 50xc2x0 C. and reaction times are typically about 1 to about 12 hours.
Compounds of formula (I) (L1 is xe2x80x94SCR12R13xe2x80x94 or xe2x80x94CR12R13Sxe2x80x94) can be intraconverted to compounds of formula (I) (L1 is S(O)CR12R13xe2x80x94, xe2x80x94SO2CR12R13xe2x80x94, xe2x80x94SCR12R13xe2x80x94, xe2x80x94CR12R13S(O)xe2x80x94, or xe2x80x94CR12R13SO2xe2x80x94) by treatement with an oxidizing agent. Representative oxidizing agents include H2O2 with acetic anhydride, and potassium peroxymonosulfate (OXONE(copyright)). Examples of solvents used in these reactions include dichloromethane, acetone, 1,2-dichloroethane, chloroform, and mixtures thereof. The reaction temperature is about 25xc2x0 C. to about 40xc2x0 C. and depends on the method chosen. Reaction times are typically about 8 hours to about 24 hours.
Compounds of formula (I) wherein L1 is xe2x80x94SO2CR12R13xe2x80x94 or xe2x80x94CR12R13SO2xe2x80x94 (R12 and R13 are hydrogen) can be intraconverted to compounds of formula (I) wherein L1 is xe2x80x94SO2CR12R13xe2x80x94 or xe2x80x94CR12R13SO2xe2x80x94 (R12 and R13 are alkyl) by treatment with a base and an alkylating agent. Representative bases include lithium hexamethyldisilazide, sodium hexamethyldisilazide, potassium hexamethyldisilazide, and lithium diisopropylamide. Representative alkylating agents include iodomethane, bromopropane, iodobutane, and the like. Examples of solvents used in these reactions include tetrahydrofuran, dioxane, diethyl ether, and methyl tert butyl ether. Reaction times are about 2 hours to about 6 hours, and reaction temperatures are typically about 0xc2x0 C. to about 30xc2x0 C.